In the brains of mice grow
the cells of man
By CARL T. HALL
San Francisco Chronicle

December 13, 2005
Tuesday

Researchers have designed mice containing fully functional human
nerve cells as a novel way to study and potentially treat neurodegenerative
diseases such as Parkinson's and Alzheimer's.

The neurons were formed in
the brains of mice that had been injected with human embryonic
stem cells as 2-week-old embryos.

Studies at the Salk Institute
for Biological Sciences showed that the human cells migrated
throughout the mouse brain and took on the traits of their mouse-cell
neighbors. The results present direct evidence that primitive
human stem cells can be cultured in the lab, be injected into
an animal, and then develop into a particular type of desired
cell.

The report appears in this
week's Proceedings of the National Academy of Sciences.

Scientists said it was the
first time cultured human embryonic stem cells have been shown
to develop into a particular type of cell in the body of another
living species.

Creation of a so-called "mouse-human
chimeric nervous system" stops well short of spawning a
mouse with a human-like cerebral cortex. In fact, all the brain
structures of the four mice used in the Salk experiments had
been formed before the human cells were injected, and less than
0.1 percent of the mice brain cells were found to be of human
origin.

Yet the new experiments approach
an ethical divide that makes some observers squeamish.

The term chimera comes from
a creature in Greek mythology that had the head of a lion on
the body of a goat. Such monstrous connotations have been tamed
somewhat in the modern era of pig valves for heart patients and
protein drugs manufactured in hamster cells.

Still, some critics of human
embryonic stem cell research argue that more attention should
be paid to the ethics and potential dangers of cutting-edge biomedical
research.

"Where are the lines,
and how do we decide where the lines are?" wondered Jennifer
Lahl, a bioethicist at the Center for Bioethics and Culture Network
in Oakland. "What if someone decides to start doing this
for art? I'm glad science has progressed to the level that we
can do this incredible stuff, but we also have to be a lot more
thoughtful about it."

The bioethical implications
aside, the findings may have broad interest in the stem cell
field because they suggest that stem cells respond to much the
same signals in mice as in humans - if not all mammals. Previous
development or "differentiation" studies of stem cells
into the various cell types of the body have been done primarily
in laboratory dishes.

Researchers now hope to discover
how brain disorders develop out of the mysterious interaction
of neurons and their surroundings.

"Is it a diseased environment
that influences nondiseased cells, or are diseased cells hurting
a healthy, intact environment?" asked Fred Gage, a Salk
Institute professor and co-head of the institute's Laboratory
of Genetics, who was senior author of the new study.

Similarly, if a drug candidate
is found, it might first be given to chimeric mice to study the
drug's effect on human cells in a living system before proceeding
to human trials.

Gage said care was taken to
ensure that the human-mouse brain experiments were done ethically
and noted that the experimental design was approved in advance
by an independent ethics review board sponsored by the Salk Institute.

Begun in 2003, the work predated
the appearance of a National Academies report on stem cell ethics,
which has become the tentative guideline of stem cell programs
including the California Institute for Regenerative Medicine,
created by Proposition 71 in 2004. Gage said a special embryonic
stem cell ethics review panel was set up at Salk as suggested
by the National Academies, and approved the experiments after
they were done.

Also, in accord with the guidelines,
the mice in the experiments were isolated in separate cages so
they couldn't breed, to avoid the possibility of creating lines
of chimeric animals. This was done even though it would be highly
unlikely that human cells - which in this case were injected
directly into the fluid-filled ventricles of the mouse brains
- would alter mouse reproductive cells.